Stabilization of Liner Implosions via a Dynamic Screw Pinch.

Magnetically driven implosions are susceptible to magnetohydrodynamic instabilities, including the magneto-Rayleigh-Taylor instability (MRTI). To reduce MRTI growth in solid-metal liner implosions, the use of a dynamic screw pinch (DSP) has been proposed [P. F. Schmit et al., Phys. Rev. Lett. 117, 205001 (2016)PRLTAO0031-900710.1103/PhysRevLett.117.205001]. In a DSP configuration, a helical return-current structure surrounds the liner, resulting in a helical magnetic field that drives the implosion. Here, we present the first experimental tests of a solid-metal liner implosion driven by a DSP. Using the 1-MA, 100-200-ns COBRA pulsed-power driver, we tested three DSP cases (with peak axial magnetic fields of 2 T, 14 T, and 20 T) and a standard z-pinch (SZP) case (with a straight return-current structure and thus zero axial field). The liners had an initial radius of 3.2 mm and were made from 650-nm-thick aluminum foil. Images collected during the experiments reveal that helical MRTI modes developed in the DSP cases, while nonhelical (azimuthally symmetric) MRTI modes developed in the SZP case. Additionally, the MRTI amplitudes for the 14-T and 20-T DSP cases were smaller than in the SZP case. Specifically, when the liner had imploded to half of its initial radius, the MRTI amplitudes for the SZP case and for the 14-T and 20-T DSP cases were, respectively, 1.1±0.3 mm, 0.7±0.2 mm, and 0.3±0.1 mm. Relative to the SZP, the stabilization obtained using the DSP agrees reasonably well with theoretical estimates.

Childhood neighborhood context and adult substance use problems: the role of socio-economic status at the age of 30 years.

OBJECTIVES: To examine whether the (a) childhood neighborhood context predicts alcohol use disorder, nicotine dependence, and cannabis use disorder symptoms at the age of 39 years; and (b) socio-economic status during young adulthood mediates these relationships. Gender differences were also examined. STUDY DESIGN: The Seattle Social Development Project is a prospective longitudinal study of 808 individuals followed up from ages 10 to 39 years in Seattle, Washington, United States. The sample was gender balanced (51% were men). METHODS: Alcohol, nicotine, and cannabis use disorder symptoms were assessed using the Diagnostic and Statistical Manual of Mental Disorders IV-based Diagnostic Interview Schedule. Childhood neighborhood data consisted of 10 neighborhood-level variables from the 1990 national census, which were consolidated using principal component analyses. Two components with eigenvalues greater than 1 were extracted-neighborhood disadvantage and neighborhood stability. Educational attainment and employment status represented socio-economic status during young adulthood. Covariates included baseline symptoms of psychopathology, baseline substance use, gender, ethnicity, and childhood socio-economic status at the family level. Negative binomial regression was used as the primary modeling strategy. Six models for each outcome measure were estimated. The first three models examined associations between two neighborhood components and each substance use outcome measure. Next, we tested the second research question by adding unemployment and college graduate indicators at the age of 30 years as potential mediators underlying the link between the childhood neighborhood context and three substance use measures. RESULTS: Study findings revealed that childhood neighborhood stability significantly reduced alcohol and cannabis use disorder symptoms nearly 3 decades later. Path analyses suggested that socio-economic status during the transition to adulthood did not influence these relationships but rather had independent effects on problematic nicotine and cannabis use. Furthermore, the effects of childhood neighborhood factors on problematic nicotine use were stronger for men. CONCLUSIONS: Neighborhood characteristics during childhood may be important factors for alcohol and cannabis use disorder symptoms among adults and nicotine dependence disorder symptoms among men. Prevention efforts that address community stability and disadvantage can and should start in childhood, with a focus on intervention targets that might gain salience later in life to discourage the development and persistence of problematic substance use in adulthood.

The cost of oropharyngeal cancer in England: A retrospective hospital data analysis.

OBJECTIVES: To estimate the total costs of treating head and neck cancers, specifically oropharyngeal, laryngeal and oral cavity cancer, in secondary care facilities in England during the period 2006/2007 to 2010/2011. DESIGN: Patient records were extracted from an English hospital database to estimate the number of patients treated for oropharyngeal, laryngeal and oral cavity cancer in England. Identified resource use was linked to published United Kingdom cost estimates to quantify the reimbursement of treatment through the Payment by Results system. SETTING: Retrospective hospital data analysis. PARTICIPANTS: From the hospital data, patient records of patients treated for oropharyngeal, laryngeal and oral cavity cancer were selected. MAIN OUTCOME MEASURES: Annual total costs of treatment, stratified by inpatient and outpatient setting and by male and female patients. RESULTS: From 2006/2007 to 2010/2011, total costs of treatment across the three head and neck cancer sites were estimated to be approximately £309 million, with 90% attributable to inpatient care (bundled costs). Oropharyngeal cancer accounted for 37% of total costs. Costs and patient numbers increased over time, largely due to a rise in oropharyngeal cancer, where total costs increased from £17.21 million to £30.32 million, with over 1400 (52%) more inpatients treated in 2010/11 compared to 2006/07. CONCLUSIONS: In 4 years, the number of patients with oropharyngeal cancer receiving some form of inpatient care increased by more than half, and associated costs increased by three quarters. This reinforces the case for prevention and early detection strategies to help contain this epidemiological and economic burden.

Socioeconomic deprivation and the burden of head and neck cancer-Regional variations of incidence and mortality in Merseyside and Cheshire, North West, England.

OBJECTIVES: The aim of this longitudinal study was to examine the distribution of head and neck cancer (HANC) disease burden across the region comparing it to national trends. DESIGN: We undertook a retrospective study of routine data combining it with indicators of deprivation and lifestyle at small geographical areas within the 9 Local Authorities (LAs) of Merseyside and Cheshire Network (MCCN) for head and neck cancers. Data from the North West of England and England were used as comparator regions. SETTING: This research was undertaken by the Cheshire and Merseyside Public Health Collaborative, UK. PARTICIPANTS: The Merseyside and Cheshire region serves a population of 2.2 million. Routine data allowed us to identify HANC patients diagnosed with cancers coded ICD C00-C14 and C30-C32 within 3 cohorts 1998-2000, 2008-2010 and 2009-2011 for our analysis. MAIN OUTCOME MEASURES: Directly age-standardised incidence rates and directly age-standardised mortality rates in the LAs and comparator regions were measured. Lifestyle and deprivation indicators were plotted against them and measured by Pearson's correlation coefficients. RESULTS: The incidence of head and neck cancer has increased across the region from 1998-2000 to 2008-2010 with a peak incidence for Liverpool males at 35/100 000 population. Certain Middle Super Output Areas contribute disproportionately to the significant effect of incidence and mortality within LAs. Income deprivation had the strongest correlation with incidence (r = .59) and mortality (r = .53) of head and neck cancer. CONCLUSION: Our study emphasises notable geographical variations within the region which need to be addressed through public health measures.

Health related quality of life following the treatment of oropharyngeal cancer by transoral laser.

In 2006, our Institution changed the treatment strategy for small volume primary oropharyngeal tumours to transoral laser microsurgery (TOLM). The main aim of this cohort study was to report the health related quality of life (HRQOL) at around 2 years following TOLM in consecutive patients treated from July 2006 through April 2013. The University of Washington Quality of Life (UW-QOL) questionnaire was administered annually up to Spring 2014 and adjusting for mortality the overall response rate was 71 % (108/153). Tonsil primary site characterised 60 % (98) of patients, base of tongue 25 % (40), soft palate 13 % (21) and others 2 %, (3). Most patients had TOLM, neck dissection and adjuvant radiotherapy, with 21 % (34) of tumours at stage 1 or 2, 25 % (40) at stage 3 and 54 % (88) at stage 4. Kaplan-Meier estimates of overall survival were 94 % at 1 year, 88 % at 2 years and 68 % at 5 years after TOLM. Three-quarters (76 %) reported their overall QOL as being good, very good or outstanding, and by domain a clear majority of patients (range 57-94 %, median 79 %) reported none or only minor problems, most notably for swallowing, chewing and speech. The main dysfunction was in saliva (39 %). In conclusion, the outcomes in TOLM for oropharyngeal squamous cell carcinoma are very encouraging. The data supports the current treatment strategy in the Unit. Further outcomes research is required to help refine patient selection to help optimise the survival and HRQOL benefit of TOLM.

Mechanisms linking high school graduation to health disparities in young adulthood: a longitudinal analysis of the role of health behaviours, psychosocial stressors, and health insurance.

OBJECTIVES: This study examined three competing mechanisms in the link between educational attainment and health among young adults: (a) a health behaviour mechanism; (b) a psychosocial stressor mechanism; and (c) a health insurance mechanism. The central research question was the pervasiveness and specificity of these mechanisms in the link between low educational attainment and health outcomes during young adulthood. STUDY DESIGN: A prospective longitudinal study was conducted with 808 men and women followed to age 33 years in the USA. METHODS: Health outcomes included major depressive disorder, obesity, chronic health conditions, and self-rated health. The focal predictor was educational attainment at age 21. The roles of the health behaviour mechanism (heavy episodic drinking, cigarette smoking, and meeting physical activity guidelines), the psychosocial stressor mechanism (stressful life events, perceived financial stress, and lack of control at work), and having health insurance (either through their employer or union or via family members) in the link between education and varying health outcomes were assessed using path analyses. RESULTS: Lack of health insurance emerged as a statistically significant explanatory factor underlying the association of education with depression and self-rated health. Health behaviours, specifically smoking and physical activity, were statistically significant intervening factors for obesity and self-rated health. CONCLUSIONS: The processes linking educational attainment to health inequalities begin unfolding during young adulthood. The salience of different mechanisms is specific to a health outcome rather than pervasive across multiple health outcomes. Public health policies with a broad spectrum of components, particularly focussing on smoking, physical activity, and lack of health insurance, are recommended to promote educational equalities in multiple health outcomes among young adults.

The use of Tisseel™ fibrin sealant in selective neck dissection--a retrospective study in a tertiary Head and Neck Surgery centre.

OBJECTIVES: To determine the feasibility of drain-free surgery in selective neck dissection (SND) by investigating the effects of the use of synthetic fibrin glue Tisseel™ on the drain output and overall wound healing. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral unit in Head and Neck surgery. PARTICIPANTS: The case notes of 30 patients who had undergone SND in levels I to IV were examined and compared. Tisseel was applied prior to wound closure in fifteen patients only. MAIN OUTCOME MEASURES: Drain output, number of days of drain in situ and total number of days of hospitalisation as well as complications rate and type between the Tisseel and non-Tisseel groups. RESULTS: Patients who had Tisseel applied in the wound had a mean drain output of 67.1 ml, which was significantly lower than 174.4 ml in patients who did not have it. Patients in the Tisseel group had the drain in situ for a shorter period and were hospitalised for fewer days than the ones in the non-Tisseel group. CONCLUSIONS: The use of Tisseel in SND resulted in lower drain output and shorter period of drain in situ and hospitalisation. There was no additional morbidity or complication associated with its use, and the initial conclusion is that this technique may have benefits not only to patient recovery but also for healthcare providers as they could potentially reduce the overall costs of surgery by reducing the length of hospital stay.

Prognostic implications of pathologically determined tumour volume in glottic carcinomas treated by transoral laser microsurgery.

OBJECTIVES: The TNM classification system for squamous cell carcinoma (SCC) of the head and neck neglects to incorporate volumetric analysis of the primary tumour. Tumour volume (TV) has been implicated prognostically in laryngeal SCC treated by primary radiotherapy (RT), but data for patients treated surgically are lacking. We evaluated such for glottic SCCs resected by transoral laser microsurgery (TLM). DESIGN: Retrospective cohort study utilising TVs calculated as the product of tumour resection dimensions and time-to-event analyses using the Kaplan-Meier method. The prognostic ability of variables was estimated using log-rank statistics, univariate Cox regression and receiver-operating characteristics analysis where appropriate. SETTING: Tertiary referral head and neck cancer centre. PARTICIPANTS: Patients undergoing primary TLM for glottic SCC with curative intent (2007-2011) with at least 12 months follow-up data. MAIN OUTCOME MEASURES: Prognostic impact of TV on local control (LC), overall survival (OS) and disease-specific survival (DSS). RESULTS: Eligible patients (n = 129) had a median follow-up of 40 months (range 14-79 months). Median TV for all cases was 300 mm(3) (range 2-19800 mm(3)). Three-year LC, OS and DSS were 92%, 92% and 98%, respectively. Tumour volume was not a significant predictor of any oncological outcome measure. Otherwise, a significant influence of pT stage on DSS was observed and of age on OS. CONCLUSIONS: In contrast to laryngeal SCC treated by RT, TV does not appear to portend oncological outcome in glottic SCC managed specifically by TLM and consequently does not warrant incorporation into current prognostic models for such patients.

Transoral laser resection versus lip-split mandibulotomy in the management of oropharyngeal squamous cell carcinoma (OPSCC): a case match study.

The objective of this study was to compare transoral laser microsurgery (TLM) with lip-split mandibulotomy (LSM) and radial forearm free-flap reconstruction, for the resection of squamous cell carcinoma of the oropharynx (SCCOP). This study is designed as a case-control study matching 24 patients treated with TLM for SCCOP with those treated with LSM. Patients were matched by age (in 5-year epochs), sex, TNM stage, tumour sub site and type of neck dissection. Each group comprised 20 males and 4 females (mean age 56 years). Seven patients treated with TLM had an elective tracheostomy compared with all patients undergoing LSM. Moreover, the time for decanulation was reduced in patients undergoing tracheostomy for TLM. Although similar rates of patients were able to swallow to some degree on discharge, 29% of patients having LSM were discharged requiring enterostomy feeding compared with 4% of patients treated using TLM. Of those able to swallow on discharge, patients who had TLM resumed swallowing in half the time taken for those having LSM. Moreover, those treated with TLM remained in hospital for half the length of time than those treated with LSM. Due to these factors, overall cost for TLM is reduced in comparison with LSM. In comparison with LSM, TLM for the treatment of SCCOP results in fewer tracheostomies and shorter time to decanulation; a quicker recovery of swallowing function and a reduced length of hospital stay. As a result of this, treatment with TLM is on average cheaper. These factors should be considered when deciding on the surgical treatment of a patient with SCCOP.

Developing work readiness in university graduates: a case study in mapping a university curriculum to work readiness domains in an Australian physiotherapy degree.

BACKGROUND: Recent research has identified six domains of work readiness: Practical Wisdom, Interpersonal Capabilities, Personal Attributes, Organisational Acumen, Profession Specific Knowledge and Skills, and Professionally Relevant Experiences. OBJECTIVE: Using a case study, the aim of this study was to demonstrate the process of curriculum mapping to evaluate the alignment of a university program to the work readiness framework. METHODS: A retrospective audit of curriculum material for one cohort of Macquarie University's Doctor of Physiotherapy (DPT) was undertaken. Curriculum was categorized as declared, delivered, or assessed, mapped to the six work readiness domains through qualitative content analysis, and then quantitatively scored and expressed as percentages of maximum possible scores per unit, and average units scores per semester. RESULTS: Mapping curriculum to a six domain work readiness framework revealed declared, delivered, and assessed curriculum within all six work readiness domains, with varying contributions across the degree. Mapping revealed that the Profession Specific Knowledge and Skills domain had the highest coverage of declared (M = 63%, SD = 12), delivered (M = 88%, SD = 11) and assessed (M = 80%, SD = 7) curriculum, highlighting a strength of the program. The Personal Attributes domain had the lowest coverage of declared (M = 5%, SD = 5), delivered (M = 48%, SD = 24) and assessed (M = 29%, SD = 20) curriculum, highlighting opportunities for development. CONCLUSION: Mapping curriculum to a work readiness framework allows universities to consider alignment, and the strength and opportunities for the improvement of work readiness within its curriculum.

Validation of a novel diagnostic standard in HPV-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV) testing in oropharyngeal squamous cell carcinoma (OPSCC) is now advocated. Demonstration of transcriptionally active high-risk HPV (HR-HPV) in fresh tumour tissue is considered to be the analytical 'gold standard'. Clinical testing has focused on formalin-fixed paraffin-embedded (FFPE) tissue at the expense of sensitivity and specificity. Recently, a novel RNA in situ hybridisation test (RNAscope) has been developed for the detection of HR-HPV in FFPE tissue; however, validation against the 'gold standard' has not been reported. METHODS: A tissue microarray comprising FFPE cores from 79 OPSCC was tested using HR-HPV RNAscope. Analytical accuracy and prognostic capacity were established by comparison with the reference test; qRT-PCR for HR-HPV on matched fresh-frozen samples. RESULTS: High-risk HPV RNAscope had a sensitivity and specificity of 97 and 93%, respectively, against the reference test. Kaplan-Meier estimates of disease-specific survival (DSS, P=0.001) and overall survival (OS, P<0.001) by RNAscope were similar to the reference test (DSS, P=0.003, OS, P<0.001) and at least, not inferior to p16 immunohistochemistry +/- HR-HPV DNA-based tests. CONCLUSION: HR-HPV RNAscope demonstrates excellent analytical and prognostic performance against the 'gold standard'. These data suggest that the test could be developed to provide the 'clinical standard' for assigning a diagnosis of HPV-related OPSCC.

Female resistance behaviour and progeny sex ratio in two Bradysia species (Diptera: Sciaridae) with paternal genome elimination.

The relationship between female mating preferences and sex allocation has received considerable theoretical and empirical support. Typically, choosier females adjust their progeny sex ratio towards sons, who inherit the attractive traits of their father. However, in species with paternal genome elimination, where male sperm do not contain the paternal genome, predictions for the direction of progeny sex ratio biases and their relationship with female choosiness are atypical. Paternal genome elimination also creates a potential for male-female conflict over sex allocation, and any influence of female mate choice on sex ratio outcomes have interesting implications for sexually antagonistic coevolution. Within the Sciaridae (Diptera) are species that produce single-sex progeny (monogenic species) and others in which progeny comprise both sexes (digenic species). Paternal genome elimination occurs in both species. We explore female mate resistance behaviour in a monogenic and digenic species of mushroom gnat from the genus Bradysia. Our experiments confirmed our theoretical predictions, revealing that in the monogenic and digenic species, females producing female-biased progeny were more likely to have resisted at least one mating attempt.

Anaesthesia for massive retrosternal thyroidectomy in a tertiary referral centre.

BACKGROUND: Retrosternal goitre (RSG) is an uncommon problem encountered rarely by anaesthetists working outside specialized head and neck (H&N) surgical units. Traditional anaesthetic teaching warns of difficult airway management in these patients. The incidence and extent of these problems is unclear. METHODS: We have performed a retrospective review of the anaesthetic management all patients with massive RSG (extending to the aortic arch or beyond) presenting for thyroidectomy at University Hospital Aintree from January 2007 to May 2012. RESULTS: Five hundred and seventy-three patients underwent a thyroidectomy procedure at Aintree University Hospitals NHS Foundation Trust (AUH) between January 2007 and May 2012. Of these, 34 cases were documented as having a RSG. Review of each patient's preoperative computerized tomography imaging identified 19 patients with massive RSG. There was one case of failed intubation. All other patients underwent uneventful tracheal intubation via direct laryngoscopy. All glands were removed through the neck with no requirement to proceed to sternotomy. There were no instances of postoperative respiratory problems or tracheomalacia. Three patients suffered recurrent laryngeal nerve (RLN) injuries. CONCLUSION: When managed within a dedicated H&N operating theatre we have found a low incidence of difficult tracheal intubation, difficult mechanical ventilation nor postoperative respiratory difficulties in patients with massive RSG and mid-tracheal compression because of benign multi-nodular goitre. Surgical complications, however, are more frequent than those associated with cervical thyroidectomy with RLN injury and postoperative bleeding more likely.

Nutlin-3, the small-molecule inhibitor of MDM2, promotes senescence and radiosensitises laryngeal carcinoma cells harbouring wild-type p53.

BACKGROUND: Primary radiotherapy (RT) is a mainstay of treatment for laryngeal squamous cell carcinoma (LSCC). Although the cure rates for early (T1) vocal cord tumours are high, RT proves ineffective in up to a third of T3 carcinomas. Moreover, RT is associated with debilitating early- and late-treatment-related toxicity, thus finding means to de-escalate therapy, while retaining/augmenting therapeutic effectiveness, is highly desirable. p53 is a key mediator of radiation responses; we therefore investigated whether Nutlin-3, a small-molecule inhibitor of MDM2 (mouse double minute 2; an essential negative regulator of p53), might radiosensitise LSCC cells. METHODS: We performed clonogenic assays to measure radiosensitivity in a panel of LSCC cell lines (for which we determined p53 mutational status) in the presence and absence of Nutlin-3. RESULTS: LSCC cells harbouring wild-type p53 were significantly radiosensitised by Nutlin-3 (P<0.0001; log-rank scale), and displayed increased cell cycle arrest and significantly increased senescence (P<0.001) in the absence of increased apoptosis; thus, our data suggest that senescence may mediate this increased radiosensitivity. CONCLUSION: This is the first study showing Nutlin-3 as an effective radiosensitiser in LSCC cells that retain wild-type p53. The clinical application of Nutlin-3 might improve local recurrence rates or allow treatment de-escalation in these patients.

Percutaneous tracheostomy: a 6 yr prospective evaluation of the single tapered dilator technique.

BACKGROUND: The single tapered dilator (STD) percutaneous dilatational tracheostomy (PDT) technique now appears to be the single most common method of performing a tracheostomy in the critical care unit (CCU). METHODS: A single-centre, prospective evaluation of all PDTs performed in an adult mixed surgical and medical CCU between November 2003 and October 2009 was done. All procedures were undertaken by critical care physicians. A proforma recorded intraoperative complications and technical difficulties encountered during the procedure; all patients were followed up for a minimum of 3 months for delayed complications. RESULTS: A tracheostomy was performed on 589 patients during the study period. PDT was attempted in 576 patients and successfully completed in 572. PDT was abandoned in four patients due to bleeding, with three of these subsequently undergoing surgical tracheostomy (ST). ST was performed in 17 patients. Intraoperative technical difficulties were encountered in 149 (26%) cases. Sixteen (3%) procedures were deemed as having early complications. A further four (0.7%) cases had significant late complications including two tracheo-innominate fistulae (TIF). Both TIF patients died as a result of their complications giving a mortality directly attributable to PDT of 0.35%. There were no differences with respect to the occurrence of complications according to grade of operator. CONCLUSIONS: PDT performed by the STD technique is a relatively safe procedure with more than 96% of procedures performed without any early or late complications. Using this technique, more than 97% of tracheostomies undertaken during the study period were performed percutaneously. Further audit at a national level is warranted to fully evaluate long-term complications after PDT.

Speech and voice outcomes in oropharyngeal cancer and evaluation of the University of Washington Quality of Life speech domain.

BACKGROUND: Radical treatment of oropharyngeal cancer can have significant impact on speech & voice outcomes. AIMS: (i) To assess the extent of speech & voice handicap in disease-free survivors of oropharyngeal squamous cell cancer. (ii) To assess the validity of the speech domain of UWQOL as a screening tool. (iii) To identify clinical characteristics associated with worse speech/voice outcome. DESIGN: Cross-sectional survey. SETTING: University Hospital Aintree, a university teaching hospital and tertiary referral centre. PATIENTS: All who were treated for oropharyngeal cancer between 1 January 1999 and 31 May 2005, were alive, disease free and willing to participate. INTERVENTIONS: Three patient-based questionnaires: University of Washington Quality of Life (UWQOL), voice handicap index (VHI) and voice related quality of life (VRQOL). Three expert-based assessments: GRBAS rating, speech intelligibility and dysarthria rating. RESULTS: Sixty-six per cent of patients participated. Median VHI score (29) & VRQOL score (15) imply mild to moderate voice impairment. 20% of patients had severe handicap (VHI score >60). Forty-eight per cent had normal voice ratings. Speech was normal in 26%, mildly impaired in 62% and significantly impaired in 12% patients (UWQOL). Correlation between UW-QOL speech domain with speech intelligibility rating was 0.52 (P < 0.001). There were clear demarcations between UW-QOL scores of 30, 70 and 100 on the voice questionnaires. Adverse speech and voice function were associated with tumour stage, radiotherapy (RT) & free-flap surgery. CONCLUSIONS: Voice & speech impairment is prevalent in >70% of oropharyngeal cancer patients. There is moderate correlation between UWQOL speech domain and speech intelligibility assessment & voice tools making it a quick and easy screening instrument. The main clinical correlates associated with adverse patient and observer rated speech and voice outcomes were tumour stage, RT and free-flap reconstruction.

The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats.

Clinical evidence indicates that positive allosteric modulators (PAMs) of GABAA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABAA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABAA receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRM-II-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10 mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100 mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for α2/3- over α1-associated GABAA receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED50 of 32 nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that α2/3-selective GABAA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABAA receptor PAMs offer an additional inroad into the management of pain.